The resistance of tumour cells to chemotherapeutics is a major factor in the failure of chemotherapy. One form of resistance to chemotherapeutics is “multi-drug resistance” where the tumour cells become cross-resistant to a variety of chemotherapeutics; for example alkaloids, anthracyclines, actinomycin D, adriamycin and colchicine. Multi-drug resistance syndrome has been correlated in many reports with the overexpression of transmembrane glycoproteins called P-glycoproteins (Pgp). Cyclosporins have been found to reverse multi-drug resistance syndrome and [3′-desoxy-3′-oxo-MeBmt]1-[Val]2-Ciclosporin in particular has been found to be effective. [3′-desoxy-3′-oxo-MeBmt]1-[Val]2-Ciclosporin and its utility is described in European patent publication No. 296 122.
The cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated undecapeptides, generally possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic activity, each to a greater or lesser degree. Cyclosporins are generally not readily soluble in aqueous media. Consequently, it is difficult to develop pharmaceutically acceptable carriers which allow delivery of the drug in sufficiently high concentrations to permit convenient use and which allow efficient and consistent absorption of the drug by the body. Often individual cyclosporins present very specific problems in relation to their administration and, in particular, in providing galenic formulations. Species specific problems also arise with regard to drug bioavailability. This is particularly the case with the compound [3′-desoxy-3′-oxo-MeBmt]1-[Val]2-Ciclosporin which presents very special problems in relation to its incorporation in galenic formulations.
To deal with the general problems of formulating cyclosporins, British patent application 2222770 A discloses galenic formulations, containing cyclosporins, that are in the form of microemulsions or microemulsion preconcentrates. These formulations comprise a hydrophilic phase, a lipophilic phase and a surfactant. The following components are described as suitable for the hydrophilic phase: Transcutol, Glycofurol and 1,2-propylene glycol. Medium chain fatty acid triglycerides are disclosed as being suitable for the lipophilic phase. Reaction products of natural or hydrogenated vegetable oils and ethylene glycol are given as surfactants. However this British patent application does not deal with the problems of formulating [3′-desoxy-3′-oxo-MeBmt]1-[Val]2-Ciclosporin which is much more lipophilic than most other cyclosporins. PCT appliction publication no. WO 93/20833 discloses surfactant-containing compositions of [3′-desoxy-3′-oxo-MeBmt]1-[Val]2-Ciclosporin in which Cremophor is a preferred surfactant.
Rapamycin is an immunosuppressive lactam macrolide produceable, for example by Streptomyces hygroscopicus. The structure of rapamycin is given in Kesseler, H., et al.; 1993; Helv. Chim. Acta; 76: 117. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailability. Moreover, rapamycin is highly insoluble in aqueous media, e.g. water, making it difficult to formulate stable galenic compositions. Numerous derivatives of rapamycin are known. Certain 16-O-substituted rapamycins are disclosed in WO 94/02136, the contents of which are incorporated herein by reference. 40-O-substituted rapamycins are described in, e.g., in U.S. Pat. No. 5,258,389 and WO 94/09010 (O-aryl and O-alkyl rapamycins); WO 92/05179 (carboxylic acid esters), U.S. Pat. No. 5,118,677 (amide esters), U.S. Pat. No. 5,118,678 (carbamates), U.S. Pat. No. 5,100,883 (fluorinated esters), U.S. Pat. No. 5,151,413 (acetals), U.S. Pat. No. 5,120,842 (silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO 94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenyl derivatives) all of which are incorporated herein by reference. 32-O-dihydro or substituted rapamycin are described, e.g., in U.S. Pat. No. 5,256,790, incorporated herein by reference.
Further rapamycin derivatives are described in PCT application number EP96/02441, for example 32-deoxorapamycin as described in Example 1, and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin as described in Examples 2 and 3. The contents of PCT application number EP96/02441 are incorporated herein by reference.
The rapamycin used in the compositions of this invention may be any rapamycin or derivative thereof, for example as disclosed above or in the above-mentioned patent applications.
Thus the rapamycin used in the compositions of this invention may be rapamycin or an O-substituted derivative in which the hydroxyl group on the cyclohexyl ring of rapamycin is replaced by —OR1 in which R1 is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl and aminoalkyl; e.g. as described in WO94/09010, for example 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin and 40-O-(2-acetaminoethyl)-rapamycin. The rapamycin derivative may be a 26- or 28-substituted derivative.
Preferred rapamycins for use in the compositions of this invention include rapamycin, 40-O-(2-hydroxy)ethyl rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-32 (S)-dihydrorapamycin. A more preferred rapamycin is 40-O-(2-hydroxy)ethyl rapamycin. Numbering of rapamycin derivatives as used herein refers to the structure disclosed as Formula A at page 4 of published PCT application WO 96/13273, the contents of which are incorporated herein by reference.
Ascomycins, of which FK-506 and ascomycin are the best known, comprise another class of lactam macrolides, many of which have potent immunosuppressive and anti-inflammatory activity. FK506 is a lactam macrolide immunosuppressant that is produced by Streptomyces tsukubaensis No 9993. The structure of FK506 is given in the appendix to the Merck Index, 11th ed. (1989) as item A5. Ascomycin is described, e.g., in U.S. Pat. No. 3,244,592. Many derivatives of ascomycin and FK-506 have been synthesized, including halogenated derivatives such as 33-epi-chloro-33-desoxy-ascomycin described in EP 427 680. Ascomycin, FK-506 and their structurally similar analogues and derivatives are termed collectively “ascomycins”.
Examples of compounds of the ascomycin or FK 506 class are those mentioned above. They include for example FK 506, ascomycin and other naturally occurring compounds. They include also synthetic analogues.
A preferred compound of the FK 506 class for use as active ingredient in the present invention is disclosed in EP 427 680, e.g. Example 66a also known as 33-epi-chloro-33-desoxy-ascomycin. Other preferred compounds are disclosed in EP 465 426, and in EP 569 337, e.g. the compound disclosed under Example 6d and Example 71 in EP 569 337. Other preferred compounds include tetrahydropyran derivatives as disclosed in EP 626 385, e.g. the compound disclosed under Example 8 in EP 626 385.